Department of Pharmacology, Rouen University Hospital and Institut National de la Sante et de la Recherche Medicale U644, Rouen Medical School, Institut Federatif de Recherche Multidisciplinaire sur les Peptides 23, Institute for Biomedical Research, University of Rouen, Rouen, France.
Hypertension. 2010 Mar;55(3):674-80. doi: 10.1161/HYPERTENSIONAHA.109.142190. Epub 2010 Jan 18.
Cytochrome-derived epoxyeicosatrienoic acids may be important endothelium-derived hyperpolarizing factors, opening calcium-activated potassium channels, but their involvement in the regulation of arterial stiffness during changes in blood flow in humans is unknown. In healthy volunteers, we measured arterial pressure, radial artery diameter, wall thickness, and flow (NIUS02) during hand skin heating in the presence of saline or inhibitors of NO synthase (N(G)-monomethyl-L-arginine), calcium-activated potassium channels (tetraethylammonium), and cytochrome epoxygenases (fluconazole). Arterial compliance and elastic modulus were calculated and fitted as functions of midwall stress to suppress the confounding influence of geometric changes. Under saline infusion, heating induced an upward shift of the compliance-midwall stress curve and a downward shift of the modulus-midwall stress curve demonstrating a decrease in arterial tone and stiffness when blood flow increases. These shifts were reduced by N(G)-monomethyl-L-arginine and abolished by the combinations of N(G)-monomethyl-L-arginine+tetraethylammonium and N(G)-monomethyl arginine+fluconazole. In parallel, in isolated mice coronary arteries, fluconazole and tetraethylammonium reduced the relaxations to acetylcholine. However, fluconazole did not affect the relaxations to the openers of calcium-activated potassium channels of small- and intermediate-conductance NS309 and of large-conductance NS1619 excluding a direct effect on these channels. Moreover, tetraethylammonium reduced the relaxations to NS1619 but not to NS309, suggesting that the endothelium-derived hyperpolarizing factor involved mainly acts on large-conductance calcium-activated potassium channels. These results show in humans that, during flow variations, arterial stiffness is regulated by the endothelium through the release of both NO and cytochrome-related endothelium-derived hyperpolarizing factor.
细胞色素衍生的环氧二十碳三烯酸可能是重要的内皮衍生超极化因子，可打开钙激活钾通道，但它们在人类血流变化时对动脉僵硬度的调节作用尚不清楚。在健康志愿者中，我们在生理盐水或一氧化氮合酶抑制剂（N(G)-单甲基-L-精氨酸）、钙激活钾通道（四乙铵）和细胞色素环氧化物酶（氟康唑）存在的情况下，测量了手部皮肤加热期间的动脉压、桡动脉直径、壁厚度和血流（NIUS02）。动脉顺应性和弹性模量被计算并拟合为中膜应力的函数，以抑制几何变化的混杂影响。在生理盐水输注下，加热引起顺应性-中膜应力曲线向上移动，模量-中膜应力曲线向下移动，表明当血流增加时，动脉张力和僵硬度降低。这些变化被 N(G)-单甲基-L-精氨酸减少，被 N(G)-单甲基-L-精氨酸+四乙铵和 N(G)-单甲基精氨酸+氟康唑的组合消除。平行地，在分离的小鼠冠状动脉中，氟康唑和四乙铵降低了对乙酰胆碱的松弛反应。然而，氟康唑对小和中等电导 NS309 和大电导 NS1619 的钙激活钾通道开放剂的松弛反应没有影响，排除了对这些通道的直接作用。此外，四乙铵降低了对 NS1619 的松弛反应，但对 NS309 没有影响，这表明涉及的内皮衍生超极化因子主要作用于大电导钙激活钾通道。这些结果表明，在人类中，在血流变化期间，动脉僵硬度通过内皮释放一氧化氮和细胞色素相关的内皮衍生超极化因子来调节。
